VTRNA2-1 : Genetic Variation, Heritable Methylation and Disease Association

is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the gene region in multiple-case breast cancer families in which methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The -mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with methylation ( < 1.5 × 10 ); however, these explained little of the methylation variation (R < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence methylation. SNP-based heritability estimates were consistent with the mQTL findings (h = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at . Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable cluster.